The present invention relates to coated tamsulosin pellets and to unit dosage forms made therefrom.
Tamsulosin is the common name for 5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-2-methoxy-benzenesulfonamide of the formula (1). It is disclosed in EP 34432 and U.S. Pat. No. 4,731,478 as a pharmaceutically active substance having alpha-adrenergic blocking activity that is useful for treatment of cardiac insufficiencies and benign prostatic hyperplasia.
(R)-tamsulosin hydrochloride is marketed under various tradenames, including FLOMAX® (Boehringer Ingelheim) in the U.S., HARNAL® (Yamanouchi) in Japan and OMNIC® (Yamanouchi) in Europe, for treatment of symptoms of benign prostatic hyperplasia (also known as BPH) such as urinary volume and frequency problems. The approved drug products include a capsule dosage form for oral administration that comprises 0.4 mg of the tamsulosin hydrochloride. The capsule provides controlled release of the tamsulosin and is a once daily dosage form, although two capsules can be used if needed; i.e. a maximum single daily administration of 0.8 mg. U.S. Pat. No. 4,772,475 is listed in the U.S. Food and Drug Administration's Approved Drug Products with Therapuetic Equivalence Evaluations (the “Orange Book”) as corresponding to FLOMAX®.
U.S. Pat. No. 4,772,475 (EP 194838, EP 533297) discloses controlled-release pharmaceutical dosage forms comprising multiple granulate units containing tamsulosin, microcrystalline cellulose and a release control agent. The granulate gradually releases tamsulosin from the granulate matrix. The patent suggests that an enteric coating is not needed.
The disclosed process for producing the granulate units comprises granulating a mixture of tamsulosin, an unit-forming inert material such as microcrystalline cellulose and a release controlling agent comprising water and/or an aqueous emulsion, suspension or gel of a water-insoluble macromolecular substance or a solution of said macromolecular substance in an aqueous organic solvent. The macromolecular substance is preferably selected from a range of acrylic polymers, commercially sold under brand name Eudragit®. The release controlling agent serves essentially also as a binder in the granulation process. The resulting granulate may be used for making final dosage forms, capsules as well as tablets.
Example 1 of U.S. Pat. No. 4,772,475 illustrates the process. After sufficiently mixing 5 g tamsulosin HCl and 470 g microcrystalline cellulose, a mixture of 83.3 g (25 g as solid component) of Eudragit L 30 D-55 and 500 g of water was added thereto and the resultant mixture was granulated by a high-speed mixer. The granules obtained were spheres having particle sizes of 0.1 to 1.5 mm, mainly 0.2 to 1.0 mm.
U.S. Pat. No. 4,772,475 also discloses that pellets of various compositions were prepared and tested for release characteristics according to standardized Pharmacopoeial method (paddle, 150 rpm). The reported results show that in one hour in simulated gastric fluid the release ranged from 16.2 to 60.4% of the active compound. Tablets made from some of the produced pellets, having 50.3 and 57.6% release, respectively, were also tested on human volunteers in comparison with conventional tablets and concentration of the active substance in blood plasma was measured. Peak plasma levels were reached 3 hours after ingestion (in comparison with 2 hours at conventional tablets), the total amount of tamsulosin in plasma being about 75% of that of the conventional tablet.
However, such release rate is generally not sufficiently for an extended-release dosage form. It would be desirable to provide an alternative, coated tamsulosin pellet having good release characteristics.